Little is known about the biomechanical or biological stimuli that initiate the degenerative process in articular cartilage leading to osteoarthritis. Nor is much known about the role aging has in the degenerative process. This proposal will use a unique mechanical explant test system (METS) to study the initiation and progression of cartilage degradation in immature, mature and aged tissue. The METS is capable of simulating joint loading, and, most important, produces cell and matrix changes found in the initial stages of osteoarthritis. These early changes include collagen rupture (fibrillation) and cell death (apoptosis) at the articular surface, in the uppermost superficial tangential zone (STZ). We hypothesize that abnormal mechanical loads initiate a pathological cascade of events that result in collagen damage and cell death in the STZ. Furthermore, we hypothesize that the initiation of the cascade may be either (1) a consequence of direct mechanical damage to the collagen fibers in the STZ, (2) an alteration of normal cell-matrix interactions (mechanical signal transduction), or (3) mechanical modification of normal cell-molecule interactions (physiochemical signal transduction). One or more of these mechanisms may be active, and we have designed our research protocol to test these hypotheses. We will study how excessive or abnormal joint loads effect the physiological function of the chondrocytes and cartilage matrix. Our specific goals are to determine the sequence of physical and cellular events that initiate the degenerative process, what biomechanical and biological mechanisms are responsible for cell signal transduction of the mechanical and physiochemical (endogeneous) stimuli, and how the normal biomechanical and physiological transduction pathways are modified by exogenous physiochemical stimuli. We will are particularly interested in the changes occurring at the articular surface, in the STZ, and how the aging process effects cell matrix response to biomechanical stimuli. In the first phase of our research we will determine the effect of abnormal and excessive mechanical loads in the initiation of the degenerative process. In the second phase, we will use the mechanical stimulus to initiate a pathological state and map the sequence of cellular and matrix events occurring throughout the entire matrix. In the last phase, we will determine the cell signaling mechanisms involved in the initiation and progression of the degradation process, and determine the role and mechanisms by which biomechanical stimuli effect endogenous and exogeneous physiochemical stimuli in the initiation or alteration of normal function and the degenerative process.